Do Phenylketonuria and Attention Deficit/Hyperactivity Disorder Share a Common Dysfunction? A “Behavioural Inhibition System” Hypothesis

Abstract

Phenylketonuria (PKU) is a well defined metabolic disorder arising from a point mutation on a single gene. This mutation disrupts the metabolism of phenylalanine, which indirectly reduces the synthesis of dopamine. Severe cognitive impairment can be prevented by dietary treatment; however, residual symptoms may be reported. These symptoms appear closely related to a more prevalent childhood disorder: Attention Deficit/Hyperactivity Disorder (ADHD). The aetiology of ADHD is a vast contrast to PKU: it seems to arise from a complex combination of genes; and it has a substantial environmental component. These two disorders provide an opportunity to compare two vastly different genotypes that seem to converge on a specific phenotype. This thesis provides a comprehensive review of the literature on PKU, including aetiology, treatment, neural pathology, cognitive deficits and electrophysiological abnormalities. Where available, studies from the ADHD literature were matched for comparison. This comparative review found distinct neural pathologies that nonetheless had points of similarity that could underlie similar superficial symptom clusters. Overlapping symptoms between PKU and ADHD included deficits in visual function, motor function, attention, working memory, planning and inhibition. It has been suggested for both disorders that many of these cognitive deficits may arise from a primary deficit of behavioural inhibition. The primary behavioural inhibition deficit in ADHD (excluding the inattentive-subtype) has been explicitly linked to the Behavioural Inhibition System proposed by Gray & McNaughton (2000). The current thesis proposes that PKU and ADHD share this dysfunction of the Behavioural Inhibition System, which leads to superficial symptoms being common to both disorders. One role of the Behavioural Inhibition System is to resolve conflict between two competing goals. Therefore, an ideal task to test this hypothesis should: 1. Be a pure measure of behavioural inhibition, unconfounded by other abilities that may be deficient in PKU and ADHD; 2: Produce conflict-specific activation of the Behavioural Inhibition System. The Stop Signal Task is one of the simplest test of behavioural inhibition and has been recently used to produce conflict-specific theta rhythm activation in healthy adults. This provides a marker of activation of the Behavioural Inhibition System. The thesis ends with the first demonstration that the Stop Signal Task can be used to produce conflict-specific theta activation in healthy children. The hypothesis that PKU and ADHD share a common dysfunction of the Behavioural Inhibition System can therefore be directly tested.